5-(2-imidazolinylamino)benzimidazole compounds useful as alpha-2 andrenoceptor agonists

ABSTRACT

The subject invention involves compounds having the following structure: ##STR1## wherein: (a) R is unsubstituted C 1  -C 3  alkanyl or alkenyl; 
     (b) R&#39; is selected from hydrogen; unsubstituted C 1  -C 3  alkanyl or alkenyl; unsubstituted C 1  -C 3  alkylthio or alkoxy; hydroxy; thiol; cyano; and halo; and 
     (c) R&#39; is selected from hydrogen, methyl, ethyl and i-propyl. 
     The subject invention also involves pharmaceutical compositions containing such novel compounds, compositions thereof and the use of such compounds for preventing or treating respiratory, ocular and/or gastrointestinal disorders.

This is a continuation-in-part of application Ser. No. 08/349,558, filedon Dec. 8, 1994, now U.S. Pat. No. 5,478,858 which is acontinuation-in-part of Ser. No. 08/169,868, filed on Dec. 17, 1993, nowabandoned.

TECHNICAL FIELD

The subject invention relates to certain substituted5-(2-imidazolinylamino)benzimidazole compounds. The compounds have beenfound to be alpha adrenoceptor agonists and are useful for treatment ofone or more of respiratory disorders.

BACKGROUND OF THE INVENTION

Information regarding alpha adrenergic receptors, agonists andantagonists, in general, and regarding compounds related in structure tothose of the subject invention are disclosed in the followingreferences: Timmermans, P.B.M.W.M., A. T. Chiu & M.J.M.C. Thoolen, "12.1α-Adrenergic Receptors", Comprehensive Medicinal Chemistry, Vol. 3,Membranes & Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press(1990), pp. 133-185; Timmermans, P.B.M.W.M. & P. A. van Zwieten,"α-Adrenoceptor Agonists and Antagonists", Drugs of the Future, Vol. 9,No. 1, (January, 1984), pp. 41-55; Megens, A.A.H.P., J. E. Leysen, F. H.L. Awouters & C. J. E. Niemegeers, "Further Validation of in vivo and invitro Pharmacological Procedures for Assessing the α₁ and α₂-Selectivity of Test Compounds: (2) α-Adrenoceptor Agonists", EuropeanJournal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans,P.B.M.W.M., A. de Jonge, M.J.M.C. Thoolen, B. Wilfred, H. Batink & P. A.van Zwieten, "Quantitative Relationships between α-Adrenergic Activityand Binding Affinity of α-Adrenoceptor Agonists and Antagonists",Journal of Medicinal Chemistry, Vol. 27 (1984) pp. 495-503; van Meel, J.C. A., A. de Jonge, P.B.M.W.M. Timmermans & P. A. van Zwieten,"Selectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1and Alpha-2 Adrenoceptors in the Normotensive Rat", The Journal ofPharmacology and Experimental Therapeutics, Vol. 219, No. 3 (1981), pp.760-767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M. Myers, C. F. C.Smith & M. R. Stillings, "Effect of 1,4-Dioxanyl Substitution on theAdrenergic Activity of Some Standard α-Adrenoreceptor Agents", EuropeanJournal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622; Chapleo, C.B., R. C. M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C.Smith, M. R. Stillings & I. F. Tulloch, "Heteroaromatic Analogues of theα₂ -Adrenoreceptor Partial Agonist Clondine", J. Med. Chem., Vol. 32(1989), pp. 1627-1630; Clare, K. A., M. C. Scrutton & N. T. Thompson,"Effects of α₂ -Adrenoceptor Agonists and of Related Compounds onAggregation of, and on Adenylate Cyclase Activity in, Human Platelets",Br. J. Pharmac., Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319issued to Danielewicz, Snarey & Thomas on Jun. 17, 1975; and U.S. Pat.No. 5,091,528 issued to Gluchowski on Feb. 25, 1992. However, manycompounds related in structure to those of the subject invention do notprovide the activity and specificity desirable when treatingrespiratory, ocular or gastrointestinal disorders.

It is particularly relevant to the subject invention that compoundsfound to be effective nasal decongestants are frequently found to haveundesirable side effects, such as causing hypertension and insomnia,particularly when administered systemically. There is a need for newdrugs which provide relief from nasal congestion without causing theseundesirable side effects.

It is an object of the subject invention to provide novel compoundshaving substantial activity in preventing or treating nasal congestion.

It is a further object of the subject invention to provide suchcompounds which do not cause hypotension, drowsiness, hypertension,insomnia or other undesirable side effects, particularly whenadministered systemically.

It is also an object of the subject invention to provide novel compoundsfor treating cough, chronic obstructive pulmonary disease (COPD) and/orasthma.

It is also an object of the subject invention to provide novel compoundsfor treating glaucoma and/or diarrhea.

It is a still further object of the subject invention to provide suchcompounds which have good activity from peroral and/or topical and/orintranasal dosing.

It is an object of the subject invention to provide such novel compoundsin pharmaceutically acceptable compositions.

It is an object of the subject invention to provide such novel compoundsin pharmaceutically acceptable compositions in combinations with otheractive which provide further theraputic benefit.

SUMMARY OF THE INVENTION

The subject invention relates compounds having the following structure:##STR2## wherein: (a) R is unsubstituted C₁ -C₃ alkanyl or alkenyl;

(b) R' is selected from hydrogen; unsubstituted C₁ -C₃ alkanyl oralkenyl; unsubstituted C₁ -C₃ alkylthio or alkoxy; hydroxy; thiol;cyano; and halo; and

(c) R" is selected from hydrogen, methyl, ethyl and i-propyl;pharmaceutical compositions containing such novel compounds, and the useof such compounds for preventing or treating other respiratory, ocularand/or gastrointestinal disorders.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, "alkanyl" means a saturated hydrocarbon substituent,straight or branched chain, unsubstituted or substituted. As usedherein, "alkenyl" means a hydrocarbon substituent with one double bond,straight or branched chain, unsubstituted or substituted. As usedherein, "alkylthio" means a substituent having the structure Q--S--,where Q is alkanyl or alkenyl.

As used herein, "alkoxy" means a substituent having the structureQ--O--, where Q is alkanyl or alkenyl.

Compounds

The subject invention involves compounds having the following structure:##STR3##

In the above structure, R is unsubstituted alkanyl or alkenyl havingfrom 1 to about 3 carbon atoms. R is preferably alkanyl. R is mostpreferably methyl or ethyl.

In the above structure, R' is selected from hydrogen; unsubstitutedalkanyl or alkenyl having from 1 to about 3 carbon atoms; unsubstitutedalkylthio or alkoxy having from 1 to about 3 carbon atoms; hydroxy;thiol; cyano; and halo. R' is preferably hydrogen. R' is also preferablyalkanyl, more preferably methyl or ethyl, most preferably methyl. R'which is alkylthio or alkoxy is preferably saturated, also preferably C₁or C₂, more preferably methylthio or methoxy. R' which is halo ispreferably chloro or bromo or fluoro, more preferably chloro orespecially fluoro.

In the above structure, R" is selected from hydrogen, methyl, ethyl andi-propyl. R" is preferably hydrogen, methyl or ethyl, more preferablyhydrogen or methyl, most preferably hydrogen.

Preferred compounds of the subject invention have the followingstructure: ##STR4## where R, R' and R" are as indicated in the followingtable:

    ______________________________________                                        Compound No.   R          R'        R"                                        ______________________________________                                        1              CH.sub.3   H         H                                         2              CH.sub.2 CH.sub.3                                                                        H         H                                         3              CH.sub.3   CH.sub.3  H                                         4              CH.sub.3   H         CH.sub.3                                  5              CH.sub.3   F         H                                         ______________________________________                                    

The compounds of the subject invention are particularly useful for thetreatment of nasal congestion associated with allergies, colds, andother nasal disorders with associated nasal congestion, as well as theirsequelae (for example, sinusitis and otitis). At the same time, it hasbeen found that undesired side effects, such as hypotension, drowsiness,hypertension, or insomnia can often be avoided. While not limited to aparticular mechanism of action, the subject compounds are believed toprovide advantages in the treatment of nasal decongestion over relatedcompounds through their ability to interact with alpha-2 adrenoceptors.The subject compounds have been found to be alpha-2 adrenoceptoragonists which cause constriction of peripheral vascular beds in theturbinates.

Particular subject compounds have no or only weak alpha-1 agonistactivity, and have little or no effect on the central nervous system,even when dosed systemically.

The compounds of the subject invention are also useful for the treatmentof ocular disorders associated with increased intraocular pressure, suchas glaucoma. The compounds are administered either perorally, ortopically as drops, gels or creams directly to the surface of themammalian eye.

The compounds of the subject invention are also useful for controllinggastrointestinal motility disorders, such as diarrhea, by antimotilityand antisecretory actions on the gastrointestinal tract.

The pharmacological activity and selectivity of the subject compoundscan be determined using published test procedures. The alpha-2selectivity of the compounds is determined by measuring receptor bindingaffinities and in vitro functional potencies in a variety of tissuesknown to possess alpha-2 and/or alpha-1 receptors. (See, e.g., TheAlpha-2 Adrenergic Receptors, L. E. Limbird, ed., Humana Press, Clifton,N.J.) The following in vivo assays are typically conducted in rodents orother species. Central nervous system activity is determined bymeasuring locomotor activity as an index of sedation. (See, e.g.,Spyraki, C. & H. Fibiger, "Clonidine-induced Sedation in Rats: Evidencefor Mediation by Postsynaptic Alpha-2 Adrenoreceptors", J. Neural.Trans., Vol. 54 (1982), pp. 153-163). Nasal decongestant activity ismeasured using rhinomanometry as an estimate of nasal airway resistance.(See, e.g., Salem, S. & E. Clemente, "A New Experimental Method forEvaluating Drugs in the Nasal Cavity", Arch. Otolarynng, Vol. 96 (1972),pp. 524-529). Antiglaucoma activity is determined by measuringintraocular pressure. (See, e.g., Potter, D., "Adrenergic Pharmacologyof Aqueous Human Dynamics", Pharmacol. Rev., Vol. 13 (1981), pp.133-153). Antidiarrheal activity is determined by measuring the abilityof the compounds to inhibit prostaglandin-induced diarrhea. (See, e.g.,Thollander, M., P. Hellstrom & T. Svensson, "Suppression of CastorOil-Induced Diarrhea by Alpha-2 Adrenoceptor Agonists", Aliment.Pharmacol. Therap., Vol. 5 (1991), pp. 255-262). Antiasthma activity isdetermined by measuring the effect of the compound onbronchoconstriction associated with pulmonary challenges such as inhaledantigens. (See, e.g., Chang, J. J. Musser & J. Hind, "Effects of a NovelLeukotriene D₄ Antagonist with 5-Lipoxygenase and CyclooxygenaseInhibitory Activity, Wy-45,911, on Leukotriene-D₄ - and Antigen-InducedBronchoconstriction in Guinea Pig", Int. Arch. Allergy Appl. Immun.,Vol. 86 (1988), pp. 48-54; and Delehunt, J., A. Perruchound, L. Yerger,B. Marchette, J. Stevenson & W. Abraham, "The Role of Slow-ReactingSubstance of Anaphylaxis in the Late Bronchial Response After AntigenChallenge in Allergic Sheep", Am. Rev. Respir. Dis., Vol. 130 (1984),pp. 748-754). Activity in cough is determined by measuring the numberand latency of the cough response to respiratory challenges such asinhaled citric acid. (See, e.g., Callaway, J. & R. King, "Effects ofInhaled Alpha-2-Adrenoceptor and GABA_(B) Receptor Agonists on CitricAcid-Induced Cough and Tidal Volume Changes in Guinea Pigs", Eur. J.Pharmacol., Vol. 220 (1992), pp. 187-195).

The compounds of the subject invention are synthesized using thefollowing general procedures: ##STR5##

In the above schemes, where R' is alkoxy or alkylthio, the correspondinghydroxy or thiol compounds are derived from the final compounds by usinga standard dealkylating procedure (Bhatt, et al., "Cleavage of Ethers",Synthesis, 1983, pp. 249-281).

SYNTHESIS EXAMPLES

The following non-limiting examples provide details for the synthesis of5-imidazolinylaminobenzimidazoles:

EXAMPLE 1 Synthesis of 4-methyl-5-(2-imidazolinylamino )benzimidazoledihydrobromide: ##STR6##

2,3-diamino-6-nitrotoluene. To a solution 3-methyl-2,4-dinitroaniline(30 g) in boiling ethanol (750 mL) is added dropwise over 90 minutes asolution of sodium sulfide nonahydrate (109.6 g) in water (750 mL). Atthe end of the addition, the mixture is refluxed for 30 minutes thenpoured into ice (2000 g) and allowed to stand until all the ice hasmelted. The mixture is then extracted with methylene chloride and theorganic layer is dried over magnesium sulfate and rotary evaporated. Theresidue is purified by flash chromatography on silica gel, eluting withmethylene chloride to afford 2,3-diamino-6-nitrotoluene as an orangesolid.

4-Methyl-5-nitrobenzimidazole. A mixture of 2,3-diamino-6-nitrotoluene(11.81 g), formic acid (88%, 390 mL) and 12N HCl (38 mL) is heated toreflux for 1 hour. The resulting mixture is cooled to room temperatureand rotary evaporated. The residue is diluted with water (200 mL), thenbasified with ammonium hydroxide (28-30%). The suspension is extractedwith ethyl acetate (3×200 mL). The combined extracts are dried overmagnesium sulfate (MgSO₄) and evaporated to afford4-methyl-5-nitrobenzimidazole as an orange solid.

1-tert-Butoxycarbonyl-4-methyl-5-nitrobenzimidazole. A suspenion of4-methyl-5-nitrobenzimidazole (11.25 g), di-tert-butyl-dicarbonate(21.58 g), triethylamine (11.7 mL) and 4-dimethylaminopyridine (DMAP)(0.1 g) in a mixture of methanol (800 mL) and ethyl acetate (400 mL) isstirred at room temperature overnight. The mixture is rotary evaporatedand the residue purified by flash chromatography on silica gel, elutingwith 10% ethyl acetate in hexane. The product-containing fractions arecombined and rotary evaporated to afford a white solid contaminated witha yellow oil. The solid is dissolved in methylene chloride (CH₂ Cl₂) andenough hexane is added to cause precipitation. The solid is filtered andwashed with 50% methylene chloride/hexane. The filtrate is rotaryevaporated and the process repeated until no more clean white solid isobtained by precipitation. The combined solid fractions are dried invacuo to afford 1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole as awhite solid.

5-Amino-1-tert-butoxycarbonyl-4-methylbenzimidazole. To a solution of1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole (8 g) in methanol(40 mL)/ethyl acetate (400 mL)is added palladium-on-carbon (Pd/C) (10%,0.5 g) and ammonium formate (7.27g). The mixture is stirred at 50° C.for 2 hours, then filtered on Celite, with methanol wash of the solids.The filtrate is rotary evaporated and the residue partitioned betweenwater and ethyl acetate. The organic layer is washed with saturatedammonium chloride, dried over magnesium sulfate, filtered and rotaryevaporated to afford pure5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole as an off-whitesolid.

1-tert-Butoxycarbonyl-4-methyl-5-benzimidazolylisothiocyanate. To asolution of di-2-pyridyl thionocarbonate (DPT) (14.3 g) and4-dimethylaminopyridine (0.1 g) in CH₂ Cl₂ (500 mL) is added dropwiseover 30 minutes a solution of5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole (7.82 g) in CH₂ Cl₂(250 mL). The mixture is stirred for 15 minutes at room temperature thenrotary evaporated. The residue is purified by flash chromatography onsilica gel, eluting with 10% ethyl acetate/hexane to afford1-tert-butoxycarbonyl-4-methyl-5-benzimidazolylisothiocyanate as a whitesolid.

N-(1-tert-Butoxycarbonyl-4-methyl-5-benzimidazolyl)-N'-2-aminoethylthiourea.A solution of1-tert-butoxycarbonyl-4-methyl-5-benzimidazolylisothiocyanate (7.0 g) inCH₂ Cl₂ (600 mL) is added dropwise over 45 minutes to ethylenediamine (8mL) in solution in CH₂ Cl₂ (200 mL). The mixture is stirred for 3 hoursat room temperature. Ether (150 mL) is added to the suspension and themixture is stirred for 10 minutes at room temperature. The solid isfiltered. The filtrate is rotary evaporated, the residue diluted withCH₂ Cl₂ and reprecipitated with ether to afford a second crop. Thecombined solids are dried overnight in vacuo to affordN-(1-tert-butoxycarbonyl-4-methyl-5-benzimidazolyl)-N'-2-aminoethylthioureaas a white solid.

1-tert-Butoxycarbonyl-4-methyl-5-(2-imidazolinylamino)benzimidazole. Amixture ofN-(1-tert-butoxycarbonyl-4-methyl-5-benzimidazolyl)-N'-2-aminoethylthiourea(2.89 g) and mercuric acetate (3.32 g) in methanol (200 mL)/chloroform(100 mL) is stirred at room temperature for 2 hours. The resulting blackmixture is filtered on Celite and the filtrate rotary evaporated. Theresidue is purified by flash chromatography on a short pad of silicagel, eluting with 10% methanol/chloroform containing 1% ammoniumhydroxide. The product-containing fractions are collected and rotaryevaporated to afford1-tert-butoxycarbonyl-4-methyl-5-(2-imidazolinylamino)benzimidazole as awhite solid.

4-Methyl-5-(2-imidazolinylamino)benzimidazole dihydrobromide. To asolution of1-tert-butoxycarbonyl-4-methyl-5-(2-imidazolinylamino)benzimidazole(2.40 g) in glacial acetic acid (50 mL) is added a solution ofhydrobromic acid in glacial acetic acid (30%, 6 mL). The mixture isstirred at room temperature and gas evolution is monitored. After thegas evolution has stopped (about 1 hour), the precipitate is filteredand washed with ether. The solid is recrystallized from methanol/etherand dried in vacuo to afford4-methyl-5-(2-imidazolinylamino)benzimidazole dihydrobromide as a palerose solid.

EXAMPLE 2 Synthesis of 4-ethyl-5-(2-imidazolinylamino)benzimidazoledihydrobromide: ##STR7##

4-ethyl-5-(2-imidazolinylamino)benzimidazole dihydrobromide is made inthe same manner as 4-methyl-5-(2-imidazolinylamino)benzimidazoledihydrobromide (see Example 1) except that2-amino-3-ethyl-4-nitroaniline is used in place of2,3-diamino-6-nitrotoluene.

EXAMPLE 3 Synthesis of 4,7-Dimethyl-5-(2-imidazolinylamino)benzimidazolesesquifumarate: ##STR8##

4,7-Dimethylbenzimidazole. A mixture of 2,3-diamino-p-xylene (5.1 g),formic acid (88%, 200 mL) and 12N HCl (20 mL) is heated to reflux for 3hours. The resulting mixture is cooled to room temperature and rotaryevaporated. The residue is diluted with water (100 mL), then basifiedwith ammonium hydroxide (28-30%). The suspension is extracted with ethylacetate (3×100 mL). The combined extracts are dried over MgSO₄ androtary evaporated to afford 4,7-dimethylbenzimidazole as a yellow solid.

4,7-Dimethyl-5-nitrobenzimidazole. To a cold (ice bath) solution of4,7-dimethylbenzimidazole (1 g) in concentrated sulfuric acid (8 mL) isadded dropwise concentrated nitric acid (0.37 mL), over 50 minutes. Themixture is stirred an additional 30 minutes in the ice bath, then pouredinto a mixture of crushed ice (30 mL) and ammonium hydroxide (30 mL).The resulting mixture is extracted with ethyl acetate. The extract isdried over MgSO₄ and rotary evaporated to afford4,7-dimethyl-5-nitrobenzimidazole as a dark tan solid.

5-Amino-4,7-dimethylbenzimidazole. To a solution of4,7-dimethyl-5-nitrobenzimidazole (1.17 g) in methanol (150 mL) is addedPd/C (10%, 0.16 g) and ammonium formate (1.31 g). The mixture is stirredat room temperature overnight, then filtered on Celite, with methanolwash of the solids. The filtrate is rotary evaporated and the residuepartitioned between water and ethyl acetate. The organic layer is washedwith saturated ammonium chloride, dried over magnesium sulfate, filteredand rotary evaporated to afford 5-amino-4,7-dimethylbenzimidazole as afoamy reddish solid.

4,7-Dimethyl-5-benzimidazolylisothiocyanate. To a solution ofdi-2-pyridyl thionocarbonate (2.29 g) and 4-dimethylaminopyridine (0.03g) in CH₂ Cl₂ (150 mL) is added dropwise over 30 minutes a solution of5-amino-4,7-dimethylbenzimidazole (0.816 g) in methanol (50 mL). Themixture is stirred for 3 hours at room temperature, then rotaryevaporated. The residue is purified by flash chromatography on silicagel, eluting with a gradient of 50% to 80% ethyl acetate/hexane toafford 4,7-dimethyl-5-benzimidazolylisothiocyanate as a white solid.

N-(4,7-Dimethyl-5-benzimidazolyl)-N'-2-aminoethylthiourea. A solution of4,7-dimethyl-5-benzimidazolylisothiocyanate (0.59 g) in CH₂ Cl₂ (50mL)/methanol (5 mL) is added dropwise over 20 minutes to ethylenediamine(1 mL) in solution in CH₂ Cl₂ (150 mL). The mixture is stirred for 2hours at room temperature. The resulting suspension is filtered and thesolid is dried overnight in vacuo to affordN-(4,7-dimethyl-5-benzimidazolyl)-N'-2-aminoethylthiourea as a whitesolid.

4,7-Dimethyl-5-(2-imidazolinylamino)benzimidazole sesquifumarate. Amixture of N-(4,7-dimethyl-5-benzimidazolyl)-N'-2-aminoethylthiourea(0.77 g) and cupric acetate (0.81 g) in methanol (100 mL) is stirred at65°-70° C. for 40 minutes. The mixture is cooled to room temperature,NaHS.xH₂ O is added and the resulting mixture is stirred for 10 minutesat room temperature. The mixture is acidified to pH=3 with 1N HCl andfiltered on Celite. The filtrate is basified to pH=9 with 50% sodiumhydroxide and rotary evaporated. The syrupy residue is diluted withwater (20 mL) and lyophilized. The solid residue is purified by flashchromatography on a short pad of silica gel, eluting first with 10%methanol/chloroform containing 0.1% ammonium hydroxide, then 30%methanol/chloroform containing 1% ammonium hydroxide. Theproduct-containing fractions are collected and rotary evaporated. Theresidue is diluted with water (5 mL) and lyophilized to afford4,7-dimethyl-5-(2-imidazolinylamino)benzimidazole as a yellow glassysolid. A fumarate salt is obtained by treating a solution of4,7-dimethyl-5-(2-imidazolinylamino)benzimidazole in methanol (20 mL)with fumaric acid (0.278 g). The mixture is heated to achievesolubilization, then cooled to room temperature. The precipitate isfiltered and recrystallized twice from methanol/water to afford4,7-dimethyl-5-(2-imidazolinylamino)benzimidazole sesquifumarate.

EXAMPLE 4 Synthesis of1,4-Dimethyl-5-(2-imidazolinylamino)benzimidazole.HOAc: ##STR9##

2,4-Dinitro-3-methyl-formanilide. To a solution of2,4-dinitro-3-methylaniline (2 g) in formic acid (99%, 10 mL) heated at55° C., is added dropwise acetic anhydride (2.5 mL), over 15 minutes.The mixture is stirred for 1 hour at 55° C. then cooled to roomtemperature and rotary evaporated. The residue is diluted with ethylacetate (100 mL), washed with saturated NaHCO₃, dried over magnesiumsulfate and rotary evaporated. The residue is purified by flashchromatography, eluting with chloroform, to afford2,4-dinitro-3-methyl-formanilide as a white solid.

N,3-Dimethyl-2,4-dinitroaniline. To a solution of2,4-dinitro-3-methylformanilide (1.15 g) in dry tetrahydrofuran (40 mL)is added borane-dimethyl sulfide complex (1.21 mL). The mixture isrefluxed for 2 hours, then cooled in an ice bath; methanol (30 mL) isadded and the stirring is maintained for 1 hour at 0° C. The mixture isacidified to pH=2 with concentrated HCl and heated to reflux for 1 hour,diluted with methanol (70 mL) and rotary evaporated. The solid residueis suspended in water (150 mL) and basified to pH=12 with concentratedNaOH. The mixture is extracted with chloroform, and the organic layer isdried over potassium carbonate and rotary evaporated. The residue ispurified by flash chromatography on silica gel, eluting with 25% ethylacetate/hexane to afford N,3-dimethyl-2,4-dinitroaniline as an orangesolid.

N,3-Dimethyl-2,4-dinitroformanilide. To a solution ofN,3-dimethyl-2,4-dinitroaniline (0.45 g) in formic acid (99%, 10mL)/chloroform (4 mL) heated to 55° C., is added dropwise, aceticanhydride (1 mL), in two portions at 1 hour intervals. The mixture isstirred for 5 hours at 55° C., then cooled to room temperature, pouredinto 1N NaOH (50 mL) and basified to pH=12 with conc. NaOH. The mixtureis extracted with methylene chloride, and the organic layer is driedover magnesium sulfate and rotary evaporated. The residue is purified byflash chromatography, eluting with chloroform, to affordN,3-dimethyl-2,4-dinitroformanilide as a white solid.

2,4-Diamino-N,3-dimethylformanilide. To a solution ofN,3-dimethyl-2,4-dinitroformanilide (0.44 g) in methanol (30 mL)/ethylacetate (10 mL) is added palladium-on-carbon (10%, 95 mg) and ammoniumformate (0.93 g), and the mixture is stirred for 2 hours at roomtemperature. The mixture is filtered on Celite, with methanol wash ofthe solids, and the filtrate is rotary evaporated. The residue ispartitioned between methylene chloride and water. The aqueous layer isextracted 4 times with methylene chloride. The combined extracts aredried over magnesium sulfate and rotary evaporated to afford2,4-diamino-N,3-dimethylformanilide as a brown solid.

5-Amino-1,4-dimethylbenzimidazole. A suspension of2,4-diamino-N,3-dimethylformanilide (0.24 g) in 2N HCl (10 mL) is heatedto reflux for 1.5 hours. The mixture is diluted with water (50 mL),basified with 1N NaOH and extracted with ethyl acetate. The organiclayer is dried over magnesium sulfate and rotary evaporated to afford5-amino-1,4-dimethylbenzimidazole.

1,4-Dimethyl-5-benzimidazolylisothiocyanate. To a solution ofdi-2-pyridyl thionocarbonate (494 mg) and 4-dimethylaminopyridine (0.01g) in methylene chloride (40 mL) is added dropwise over 30 minutes, asolution of 5-amino-1,4-dimethylbenzimidazole (176 mg) in methylenechloride (20 mL). The mixture is stirred for 3 hours at roomtemperature, then rotary evaporated. The residue is purified by flashchromatography on silica gel, eluting with 50% ethyl acetate/hexane, toafford 1,4-dimethyl-5-benzimidazolylisothiocyanate as a white solid.

1,4-Dimethyl-5-(2-imidazolinylamino)benzimidazole.HOAc. A solution of1,4-dimethyl-5-benzimidazolylisothiocyanate (210 mg) in methylenechloride (40 mL) is added dropwise over 20 minutes to ethylenediamine(0.35 mL) in solution in methylene chloride (100 mL). The mixture isstirred for 1 hour at room temperature, then rotary evaporated. Theresidue is dissolved in methanol (70 mL), mercuric acetate (395 mg) isadded, and the mixture is stirred at room temperature for 2 hours. Theresulting black suspension is filtered on Celite with methanol wash ofthe solids. The filtrate is rotary evaporated, and the residue ispurified by flash chromatography on silica gel, eluting with 10%methanol/chloroform containing 0.1% of ammonium hydroxide. Theproduct-containing fractions are combined and rotary evaporated to yield1,4-dimethyl-5-(2-imidazolinylamino)benzimidazole.HOAc.

EXAMPLE 5 Synthesis of7-fluoro-4-methyl-5-(2-imidazolinylamino)benzimidazole: ##STR10##

2,3-Dinitro-4-fluorotoluene. Fuming sulfuric acid (180 mL) is addeddropwise to 4-fluoro-2-nitrotoluene (50.21 g) under an argon atmosphere.The internal temperature of the mixture is maintained at 0°-5° C. usingan ice/sodium chloride bath. A preformed (ice bath) mixture of fumingnitric acid (30 mL) and fuming sulfuric acid (90 mL) is added dropwiseto the previous solution over three hours. The reaction is then allowedto warm to room temperature. After stirring at room temperature for twohours, the mixture is poured slowly into ice and the products areextracted with methylene chloride (4×500 mL). The combined extracts aredried over magnesium sulfate, filtered and rotary evaporated. The crudeproduct is purified by flash chromatography on silica gel, eluting with5% ethyl acetate/hexane to afford 2,3-dinitro-4-fluorotoluene as a paleyellow solid.

4-Fluoro-7-methylbenzimidazole. A suspension of2,3-dimethyl-4-fluorotoluene (1 g), iron powder (1.95 g) andpalladium-on-carbon (10%, 150 mg) in formic acid (99%, 25 mL) is heatedto reflux for 2.5 hours. The resulting mixture is filtered throughCelite, with methanol wash of the solids. The filtrate is rotaryevaporated and the residue partitioned between water and ethyl acetate.The organic layer is dried over magnesium sulfate, filtered and rotaryevaporated to afford 4-fluoro-7-methylbenzimidazole as an off-whitesolid.

7-Fluoro-4-methyl-5-nitrobenzimidazole. To a cold (ice bath) solution of4-fluoro-7-methylbenzimidazole (734 mg) in concentrated sulfuric acid(10 mL) is added dropwise concentrated nitric acid (0.22 mL) over 1hour. The mixture is stirred an additional 15 minutes in the ice bath,then poured in a mixture of crushed ice (20 mL) and ammonium hydroxide(20 mL). The resulting mixture is extracted with ethyl acetate. Theextract is dried over magnesium sulfate, filtered and rotary evaporatedto afford 7-fluoro-4-methyl-5-nitrobenzimidazole as a pale yellow solid.

1-tert-Butoxycarbonyl-7-fluoro-4-methyl-5-nitrobenzimidazole. Asuspension of 7-fluoro-4-methyl-5-nitrobenzimidazole (0.556 g)di-tert-butyldicarbonate (0.870 g), triethylamine (0.475 mL) and4-dimethylaminopyridine (0.01 g)in ethyl acetate (100 mL) is stirred atroom temperature overnight. The mixture is rotary evaporated and theresidue purified by flash chromatography on silica gel, eluting with 10%ethyl acetate/hexane to afford1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-nitrobenzimidazole as anoff-white solid.

5-Amino-1-tert-butoxycarbonyl-7-fluoro-4-methylbenzimidazole. To asolution of 1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-nitrobenzimidazole(0.776 g) in methanol (100 mL)/ethyl acetate (50 mL) is addedpalladium-on-carbon (10%, 0.1 g) and ammonium formate (0.663 g). Themixture is stirred at room temperature for 5 hours, then filtered onCelite, with methanol wash of the solids. The filtrate is rotaryevaporated and the residue partitioned between water and ethyl acetate.The organic layer is dried over magnesium sulfate, filtered and rotaryevaporated. The residue is purified by flash chromatography on silicagel, eluting with 25% ethyl acetate/hexane to afford5-amino-1-tert-butoxycarbonyl-7-fluoro-4-methylbenzimidazole as a yellowoil.

1-tert-Butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolylisothiocyanate.To a solution of di-2-pyridyl thionocarbonate (0.393 mg) and4-dimethylaminopyridine (0.01 g) in methylene chloride (100 mL) is addeddropwise over 30 minutes a solution of5-amino-1-tert-butoxycarbonyl-7-fluoro-4-methylbenzimidazole (0.409 g)in methylene chloride (70 mL). The mixture is stirred at roomtemperature for 3 hours then rotary evaporated. The residue is purifiedby flash chromatography on silica gel, eluting with 10% ethylacetate/hexane to afford1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolylisothiocyanateas a white solid.

N-(1-tert-Butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolyl)-N'-2-aminoethylthiourea.A solution of1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolylisothiocyanate(0.42 g) in methylene chloride (50 mL) is added dropwise over 15 minutesto 1,2-ethylenediamine (0.45 mL) in solution in methylene chloride (100mL). The mixture is stirred for 10 minutes at room temperature, thenrotary evaporated. The residue is triturated for 30 minutes with ether(100 mL). The resulting white suspension is filtered and the solid isdried in vacuo overnight.

7-Fluoro-4-methyl-5-(2-imidazolinylamino)benzimidazole. A mixture ofN-(1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolyl)-N'-2-aminoethylthio-urea(0.5 g) and mercuric acetate (0.52 g) in methanol (150 mL) is stirred atroom temperature for 1 hour. The resulting black mixture is filtered onCelite with methanol wash of the solids. The filtrate is rotaryevaporated and the residue filtered through a short pad of silica gel,eluting 25% methanol in chloroform containing 1% of ammonium hydroxide.The product-containing fractions are rotary evaporated, the residuediluted with water (15 mL), filtered through a plug of glass wool andlyophilized to afford7-fluoro-4-methyl-5-(2-imidazolinylamino)benzimidazole as a pale yellowsolid.

Compositions

Another aspect of the subject invention is compositions which comprise asafe and effective amount of a subject compound, or apharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable carrier. As used herein, "safe and effectiveamount" means an amount of the subject compound sufficient tosignificantly induce a positive modification in the condition to betreated, but low enough to avoid serious side effects (at a reasonablebenefit/risk ratio), within the scope of sound medical judgement. A safeand effective amount of the subject compound will vary with the age andphysical condition of the patient being treated, the severity of thecondition, the duration of the treatment, the nature of concurrenttherapy, the particular pharmaceutically-acceptable carrier utilized,and like factors within the knowledge and expertise of the attendingphysician.

Compositions of the subject invention preferably comprise from about0.0001% to about 99% by weight of the subject compound, more preferablyfrom about 0.01% to about 90%; also preferably from about 10% to about50%, also preferably from about 5% to about 10%, also preferably fromabout 1% to about 5%, and also preferably from about 0.1% to about 1%.

In addition to the subject compound, the compositions of the subjectinvention contain a pharmaceutically-acceptable carrier. The term"pharmaceutically-acceptable carrier", as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to a human or lower animal. Theterm "compatible", as used herein, means that the components of thecomposition are capable of being commingled with the subject compound,and with each other, in a manner such that there is no interaction whichwould substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use situations. Pharmaceutically-acceptablecarriers must, of course, be of sufficiently high purity andsufficiently low toxicity to render them suitable for administration tothe human or lower animal being treated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tweens®; wetting agents, such sodium lauryl sulfate; coloringagents; flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

If the subject compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4.

The preferred mode of administering the subject compounds is perorally.The preferred unit dosage form is therefore tablets, capsules, lozenges,chewable tablets, and the like. Such unit dosage forms comprise a safeand effective amount of the subject compound, which is preferably fromabout 0.01 mg to about 200 mg, more preferably from about 0.1 mg toabout 50 mg, more preferably still from about 0.5 mg to about 25 mg,also preferably from about 1 mg to about 10 mg. Thepharmaceutically-acceptable carrier suitable for the preparation of unitdosage forms for peroral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical for the purposes of the subjectinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Such liquid oral compositions preferably comprise from about 0.001% toabout 5% of the subject compound, more preferably from about 0.01% toabout 0.5%. Typical components of carriers for syrups, elixirs,emulsions and suspensions include ethanol, glycerol, propylene glycol,polyethylene glycol, liquid sucrose, sorbitol and water. For asuspension, typical suspending agents include methyl cellulose, sodiumcarboxymethyl cellulose, Avicel® RC-591, tragacanth and sodium alginate;typical wetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual and buccal dosage forms. Such compositionstypically comprise one or more of soluble filler substances such assucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

A preferred mode of administering the subject compounds is topically tothe site where activity is desired: intranasal doses for nasaldecongestion, inhalants for asthma, eye drops, gels and creams forocular disorders, and peroral doses for gastrointestinal disorders.

Preferred compositions of the subject invention include aqueoussolutions comprising a safe and effective amount of a subject compoundintended for topical intranasal administration. Such compositionspreferably comprise from about 0.001% to about 5% of a subject compound,more preferably from about 0.01% to about 0.5%. Such compositions alsotypically include safe and effective amounts of preservatives, such asbenzalkonium chloride and thimerosal; buffers such as phosphate andacetate; tonicity agents such as sodium chloride; antioxidants such asascorbic acid; aromatic agents; and acids and bases to adjust the pH ofthese aqueous compositions as needed.

Preferred compositions of the subject invention include aqueoussolutions, suspensions, and dry powders comprising a safe and effectiveamount of a subject compound intended for atomization and topicalinhalation administration. Such compositions preferably comprise fromabout 0.1% to about 50% of a subject compound, more preferably fromabout 1% to about 20%. Such compositions are typically contained in acontainer with attached atomizing means. Such compositions alsotypically include propellants such as chlorofluorocarbons 12/11 and12/114; solvents such as water, glycerol and ethanol; stabilizers suchas ascorbic acid, sodium metabisulfite; preservatives such ascetylpyridinium chloride and benzalkonium chloride; tonicity adjustorssuch as sodium chloride; and flavoring agents such as sodium saccharin.

Preferred compositions of the subject invention include aqueoussolutions comprising a safe and effective amount of a subject compoundintended for topical intraocular administration. Such compositionspreferably comprise from about 0.0001% to about 5% of a subjectcompound, more preferably from about 0.01% to about 0.5%. Suchcompositions also typically include one or more of preservatives, suchas benzalkonium chloride, thimerosal, phenylmercuric acetate; vehicles,such as poloxamers, modified celluloses, povidone and purified water;tonicity adjustors, such as sodium chloride, mannitol and glycerin;buffers such as acetate, citrate, phosphate and borate; antioxidantssuch as sodium metabisulfite, butylated hydroxy toluene and acetylcysteine; acids and bases may be used to adjust the pH of theseformulations as needed.

Preferred compositions of the subject invention include solids, such astablets and capsules, and liquids, such as solutions, suspensions andemulsions (preferably in soft gelatin capsules), comprising a safe andeffective amount of a subject compound intended for topicaladministration to the gastrointestinal tract by peroral administration.Such compositions preferably comprise from about 0.01 mg to about 100 mgper dose, more preferably from about 0.1 mg to about 5 mg per dose. Suchcompositions can be coated by conventional methods, typically with pH ortime-dependent coatings, such that the subject compound is released inthe gastrointestinal tract in the vicinity of the desired topicalapplication, or at various times to extend the desired action. Suchdosage forms typically include, but are not limited to, one or more ofcellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl cellulose phthalate, ethyl cellulose, Eudragit® coatings, waxesand shellac.

Compositions of the subject invention may optionally include other drugactives. Non-limiting examples of drug actives which may be incorporatedin these compositions, include:

Antihistamines, including;

Hydroxyzine preferably at a dosage range of from about 25 to about 400mg; Doxylamine, preferably at a dosage range of from about 3 to about 75mg; Pyrilamine, preferably at a dosage range of from about 6.25 to about200 mg; Chlorpheniramine, preferably at a dosage range of from about 1to about 24 mg; Phenindamine, preferably at a dosage range of from about6.25 to about 150 mg; Dexchlorpheniramine, preferably at a dosage rangeof from about 0.5 to about 12 mg; Dexbrompheniramine, preferably at adosage range of from about 0.5 to about 12 mg; Clemastine, preferably ata dosage range of from about 1 to about 9 mg; Diphenhydramine,preferably at a dosage range of from about 6.25 to about 300 mg;Azelastine, preferably at a dosage range of from about 140 to about1,680 ug (when dosed intranasally); 1 to about 8 mg (when dosed orally);Acrivastine, preferably at a dosage range of from about 1 to about 24mg; Levocarbastine (which can be dosed as an intranasal or ocularmedicament), preferably at a dosage range of from about 100 to about 800ug; Mequitazine, preferably at a dosage range of from about 5 to about20 mg; Astemizole, preferably at a dosage range of from about 5 to about20 mg; Ebastine;Loratadine, preferably at a dosage range of from about 5to about 40 mg; Cetirizine, preferably at a dosage range of from about 5to about 20 mg; Terfenadine, preferably at a dosage range of from about30 to about 480 mg; Terfenadine metabolites; Promethazine, preferably ata dosage range of from about 6.25 to about 50 mg; Dimenhydrinate,preferably at a dosage range of from about 12.5 to about 400 mg;Meclizine, preferably at a dosage range of from about 6.25 to about 50mg; Tripelennamine, preferably at a dosage range of from about 6.25 toabout 300 mg; Carbinoxamine, preferably at a dosage range of from about0.5 to about 16 mg; Cyproheptadine, preferably at a dosage range of fromabout 2 to about 20 mg; Azatadine, preferably at a dosage range of fromabout 0.25 to about 2 mg; Brompheniramine, preferably at a dosage rangeof from about 1 to about 24 mg; Triprolidine, preferably at a dosagerange of from about 0.25 to about 10 mg; Cyclizine, preferably at adosage range of from about 12.5 to about 200 mg; Thonzylamine,preferably at a dosage range of from about 12.5 to about 600 mg;Pheniramine, preferably at a dosage range of from about 3 to about 75mg; Cyclizine, preferably at a dosage range of from about 12.5 to about200 mg and others;

Antitussives, including;

Codeine, preferably at a dosage range of from about 2.5 to about 120 mg;Hydrocodone, preferably at a dosage range of from about 2.5 to about 40mg; Dextromethorphan, preferably at a dosage range of from about 2.5 toabout 120 mg; Noscapine, preferably at a dosage range of from about 3 toabout 180 mg; Benzonatate, preferably at a dosage range of from about100 to about 600 mg; Diphenhydramine, preferably at a dosage range offrom about 12.5 to about 150 mg; Chlophedianol, preferably at a dosagerange of from about 12.5 to about 100 mg; Clobutinol, preferably at adosage range of from about 20 to about 240 mg; Fominoben, preferably ata dosage range of from about 80 to about 480 mg; Glaucine; Pholcodine,preferably at a dosage range of from about 1 to about 40 mg; Zipeprol,preferably at a dosage range of from about 75 to about 300 mg;Hydromorphone, preferably at a dosage range of from about 0.5 to about 8mg; Carbetapentane, preferably at a dosage range of from about 15 toabout 240 mg; Caramiphen, Levopropoxyphene, preferably at a dosage rangeof from about 25 to about 200 mg and others;

Antiinflammatories, preferably Non-Steroidal Anti-inflammatories,(NSAIDS) including;

Ibuprofen, preferably at a dosage range of from about 50 to about 3,200mg; Naproxen, preferably at a dosage range of from about 62.5 to about1,500 mg; Sodium naproxen, preferably at a dosage range of from about110 to about 1,650 mg; Ketoprofen, preferably at a dosage range of fromabout 25 to about 300 mg; Indoprofen, Indomethacin, preferably at adosage range of from about 25 to about 200mg; Sulindac, preferably at adosage range of from about 75 to about 400 mg; Diflunisal, preferably ata dosage range of from about 125 to about 1,500 mg; Ketorolac,preferably at a dosage range of from about 10 to about 120 mg;Piroxicam, preferably at a dosage range of from about 10 to about 40 mg;Aspirin, preferably at a dosage range of from about 80 to about 4,000mg; Meclofenamate, preferably at a dosage range of from about 25 toabout 400 mg; Benzydamine, preferably at a dosage range of from about 25to about 200 mg; Carprofen, preferably at a dosage range of from about75 to about 300 mg; Diclofenac, preferably at a dosage range of fromabout 25 to about 200 mg; Etodolac, preferably at a dosage range of fromabout 200 to about 1,200 mg; Fenbufen, preferably at a dosage range offrom about 300 to about 900 mg; Fenoprofen, preferably at a dosage rangeof from about 200 to about 3,200 mg; Flurbiprofen, preferably at adosage range of from about 50 to about 300 mg; Mefenamic acid,preferably at a dosage range of from about 250 to about 1,500 mg;Nabumetone, preferably at a dosage range of from about 250 to about2,000 mg; Phenylbutazone, preferably at a dosage range of from about 100to about 400 mg; Pirprofen, preferably at a dosage range of from about100 to about 800 mg; Tolmetin, preferably at a dosage range of fromabout 200 to about 1,800 mg and others;

Analgesics, including;

Acetaminophen, preferably at a dosage range of from about 80 to about4,000 mg; and others:

Expectorants/Mucolytics, including;

Guaifenesin, preferably at a dosage range of from about 50 to about2,400mg; N-Acetylcysteine, preferably at a dosage range of from about100 to about 600 mg; Ambroxol, preferably at a dosage range of fromabout 15 to about 120 mg; Bromhexine, preferably at a dosage range offrom about 4 to about 64 mg; Terpin hydrate, preferably at a dosagerange of from about 100 to about 1,200 mg; Potassium iodide, preferablyat a dosage range of from about 50 to about 250 mg and others;

Atropinics, preferably intranasally or orally administered atropinics,including;

Ipratroprium (preferably intranasally), preferably at a dosage range offrom about 42 to about 252 ug; Atropine sulfate (preferably oral),preferably at a dosage range of from about 10 to about 1,000 ug;Belladonna (preferably as an extract), preferably at a dosage range offrom about 15 to about 45 mg equivalents; Scopolamine, preferably at adosage range of from about 400 to about 3,200 ug; Scopolaminemethobromide, preferably at a dosage range of from about 2.5 to about 20mg; Homatropine methobromide, preferably at a dosage range of from about2.5 to about 40 mg; Hyoscyamine (preferably oral), preferably at adosage range of from about 125 to about 1,000 ug; Isopropramide(preferably oral), preferably at a dosage range of from about 5 to about20 mg; Orphenadrine (preferably oral), preferably at a dosage range offrom about 50 to about 400 mg; Benzalkonium chloride (preferablyintranasally) preferably a 0.005 to about 0.1% solution and others;

Mast Cell Stabilizers, preferably intranasally, or orally administeredmast cell stabilizers, including;

Cromalyn, preferably at a dosage range of from about 10 to about 60 mg;Nedocromil, preferably at a dosage range of from about 10 to about 60mg; Oxatamide, preferably at a dosage range of from about 15 to about120 mg; Ketotifen, preferably at a dosage range of from about 1 to about4 mg; Lodoxamide, preferably at a dosage range of from about 100 toabout 3,000 ug and others;

LT Antagonists, including Zileuton and others;

Methylxanthines, including;

Caffeine, preferably at a dosage range of from about about 65 to about600 mg; Theophyllene, preferably at a dosage range of from about 25 toabout 1,200 mg; Enprofylline; Pentoxifylline, preferably at a dosagerange of from about 400 to about 3,600 mg; Aminophylline, preferably ata dosage range of from about 50 to about 800 mg; Dyphylline, preferablyat a dosage range of from about 200 to about 1,600 mg and others;

Antioxidants or radical inhibitors, including;

Ascorbic acid, preferably at a dosage range of from about 50 to about10,000 mg; Tocopherol, preferably at a dosage range of from about 50 toabout 2,000 mg; Ethanol, preferably at a dosage range of from about 500to about 10,000 mg and others;

Steroids, preferably intranasally administered steroids, including:

Beclomethasone, preferably at a dosage range of from about 84 to about336 ug; Fluticasone, preferably at a dosage range of from about 50 toabout 400 ug; Budesonide, preferably at a dosage range of from about 64to about 256 ug; Mometasone; Triamcinolone, preferably at a dosage rangeof from about 110 to about 440 ug; Dexamethasone, preferably at a dosagerange of from about 168 to about 1,008 ug; Flunisolide, preferably at adosage range of from about 50 to about 300 ug; Prednisone (preferablyoral), preferably at a dosage range of from about 5 to about 60 mg;Hydrocortisone (preferably oral), preferably at a dosage range of fromabout 20 to about 300 mg and others;

Bronchodilators, preferably for inhalation, including;

Albuterol, preferably at a dosage range of from about 90 to about 1,080ug; 2 to about 16 mg (if dosed orally); Epinephrine, preferably at adosage range of from about 220 to about 1,320 ug; Ephedrine, preferablyat a dosage range of from about 15 to about 240 mg (if dosed orally);250 to about 1,000 ug (if dosed intranasally); Metaproterenol,preferably at a dosage range of from about 65 to about 780 ug or 10 toabout 80 mg if dosed orally; Terbutaline, preferably at a dosage rangeof from about 200 to about 2,400 ug; 2.5 to about 20 mg if dosed orally;Isoetharine, preferably at a dosage range of from about 340 to about1,360 ug; Pirbuterol, preferably at a dosage range of from about 200 toabout 2,400 ug; Bitolterol, preferably at a dosage range of from about370 to about 2,220 ug; Fenoterol, preferably at a dosage range of fromabout 100 to about 1,200 ug; 2.5 to about 20 mg (if dosed orally);Rimeterol, preferably at a dosage range of from about 200 to about 1,600ug; Ipratroprium, preferably at a dosage range of from about 18 to about216 ug (inhalation) and others; and

Antivirals, including;

Amantadine, preferably at a dosage range of from about 50 to about 200mg; Rimantadine, preferably at a dosage range of from about 50 to about200 mg; Enviroxime; Nonoxinols, preferably at a dosage range of fromabout 2 to about 20 mg (preferably an intranasal form); Acyclovir,preferably at a dosage range of from about 200 to about 2,000 mg (oral);1 to about 10 mg (preferably an intranasal form); Alpha-lnterferon,preferably at a dosage range of from about 3 to about 36 MIU;Beta-Interferon, preferably at a dosage range of from about 3 to about36 MIU and others;

Ocular Drug actives:

acetylcholinesterase inhibitors, e.g., echothiophate from about 0.03% toabout 0.25% in topical solution and others; and

Gastrointestinal actives:

antidiarrheals, e.g., Ioperamide from about 0.1 mg to about 1.0 mg perdose, and bismuth subsalicylate from about 25 mg to about 300 mg perdose and others.

Of course, clearly contemplated and included in the description aboveare the acid or base addition salts, esters, metabolites, steoisomersand enatiomers of these preferred actives, as well as analogues to theseactives that are safe and effective. It is also recognized that anactive may be useful for more than one of the above uses, and these usesare clearly contemplated as well. This overlap is recognized in the artand adjusting dosages and the like to fit the indication is well withinthe perview of the skilled medical practitioner.

Methods

Another aspect of the subject invention involves methods for preventingor treating nasal congestion by administering a safe and effectiveamount of a subject compound to a human or lower animal experiencing orat risk of experiencing nasal congestion. Such nasal congestion may beassociated with human diseases or disorders which include, but are notlimited to, seasonal allergic rhinitis, acute upper respiratory viralinfections, sinusitis, perennial rhinitis, and vasomotor rhinitis. Eachadministration of a dose of the subject compound preferably administersa dose within the range of from about 0.001 mg/kg to about 10 mg/kg of acompound, more preferably from about 0.01 mg/kg to about 5 mg/kg, morepreferably still from about 0.1 mg/kg to about 1 mg/kg. Peroraladministration of such doses is preferred. The frequency ofadministration of a subject compound according to the subject inventionis preferably from about once to about six times daily, more preferablyfrom about 2 times to about 4 times daily. Such doses and frequenciesare also preferred for treating other respiratory conditions, such asotitis media, cough, COPD and asthma.

Another aspect of the subject invention involves methods for preventingor treating glaucoma by administering a safe and effective amount of asubject compound to a human or lower animal experiencing or at risk ofexperiencing glaucoma. Each administration of a dose of the subjectcompound preferably administers a dose within the range of from about0.01 μg/kg to about 10 mg/kg of a compound, more preferably from about0.001 mg/kg to about 1 mg/kg, more preferably still from about 0.01mg/kg to about 0.1 mg/kg. Intraocular administration of such doses ispreferred. The frequency of administration of a subject compoundaccording to the subject invention is preferably from about once toabout six times daily, more preferably from about 2 times to about 4times daily.

Another aspect of the subject invention involves methods for preventingor treating functional bowel disorders, such as diarrhea, byadministering a safe and effective amount of a subject compound to ahuman or lower animal experiencing or at risk of experiencing diarrhea.Each administration of a dose of the subject compound preferablyadministers a dose within the range of from about 0.001 mg/kg to about10 mg/kg of a compound, more preferably from about 0.01 mg/kg to about 5mg/kg, more preferably still from about 0.1 mg/kg to about 1 mg/kg.Peroral administration of such doses is preferred. The frequency ofadministration of a subject compound according to the subject inventionis preferably from about once to about six times daily, more preferablyfrom about 2 times to about 4 times daily.

Composition and Method Examples

The following non-limiting examples illustrate the compositions andmethods of use of the subject invention.

EXAMPLE A Oral Table Composition

    ______________________________________                                                                Amount per tablet                                     Ingredient              (mg)                                                  ______________________________________                                        Subject Compound 4      20.0                                                  Microcrystalline cellulose (Avicel PH 102 ®)                                                      80.0                                                  Dicalcium phosphate     96.0                                                  Pyrogenic silica (Cab-O-Sil ®)                                                                    1.0                                                   Magnesium stearate      3.0                                                   Total =                 200.0                                                 ______________________________________                                    

One tablet is swallowed by a patient with nasal congestion. Thecongestion is substantially diminished.

EXAMPLE B Chewable Tablet Composition

    ______________________________________                                                                Amount per tablet                                     Ingredient              (mg)                                                  ______________________________________                                        Subject Compound 1      15.0                                                  Mannitol                255.6                                                 Microcrystalline cellulose (Avicel PH 101 ®)                                                      100.8                                                 Dextrinized sucrose (Di-Pac ®)                                                                    199.5                                                 Imitation orange flavor 4.2                                                   Sodium saccharin        1.2                                                   Stearic acid            15.0                                                  Magnesium stearate      3.0                                                   FD&C Yellow #6 dye      3.0                                                   Pyrogenic silica (Cab-O-Sil ®)                                                                    2.7                                                   Total =                 600.0                                                 ______________________________________                                    

One tablet is chewed and swallowed by a patient with nasal congestion.The congestion is substantially reduced.

EXAMPLE C Sublingual Tablet Composition

    ______________________________________                                                                Amount per tablet                                     Ingredient              (mg)                                                  ______________________________________                                        Subject Compound 5      2.00                                                  Mannitol                2.00                                                  Microcrystalline cellulose (Avicel PH 101 ®)                                                      29.00                                                 Mint flavorants         0.25                                                  Sodium saccharin        0.08                                                  Total =                 33.33                                                 ______________________________________                                    

One tablet is placed under the tongue of a patient with nasal congestionand allowed to dissolve. The congestion is rapidly and substantiallydiminished.

EXAMPLE D Intranasal Solution Composition

    ______________________________________                                        Ingredient       Composition (% w/v)                                          ______________________________________                                        Subject Compound 3                                                                             0.20                                                         Benzalkonium chloride                                                                          0.02                                                         Thimerosal       0.002                                                        d-Sorbitol       5.00                                                         Glycine          0.35                                                         Aromatics        0.075                                                        Purified water   q.s.                                                         Total =          100.00                                                       ______________________________________                                    

One-tenth of a mL of the composition is sprayed from a pump actuatorinto each nostril of a patient with nasal congestion. The congestion issubstantially diminished.

EXAMPLE E Intranasal Gel Composition

    ______________________________________                                        Ingredient          Composition (% w/v)                                       ______________________________________                                        Subject Compound 1  0.10                                                      Benzalkonium chloride                                                                             0.02                                                      Thimerosal          0.002                                                     Hydroxypropyl methylcellulose                                                                     1.00                                                      (Metolose 65SH4000 ®)                                                     Aromatics           0.06                                                      Sodium chloride (0.65%)                                                                           q.s.                                                      Total =             100.00                                                    ______________________________________                                    

One-fifth of a mL of the composition is applied as drops from a dropperinto each nostril of a patient with nasal congestion. The congestion issubstantially reduced.

EXAMPLE F Inhalation Aerosol Composition

    ______________________________________                                        Ingredient       Composition (% w/v)                                          ______________________________________                                        Subject Compound 2                                                                             5.0                                                          Alcohol          33.0                                                         Ascorbic acid    0.1                                                          Menthol          0.1                                                          Sodium Saccharin 0.2                                                          Propellant (F12, F114)                                                                         q.s.                                                         Total =          100.0                                                        ______________________________________                                    

Two-puffs of the aerosol composition is inhaled from a metered-doseinhaler by a patient with asthma. The asthmatic condition is effectivelyrelieved.

EXAMPLE G Topical Ophthalmic Composition

    ______________________________________                                        Ingredient            Composition (% w/v)                                     ______________________________________                                        Subject Compound 5    0.10                                                    Benzalkonium chloride 0.01                                                    EDTA                  0.05                                                    Hydroxyethylcellulose (Natrosol M ®)                                                            0.50                                                    Sodium metabisulfite  0.10                                                    Sodium chloride (0.9%)                                                                              q.s.                                                    Total =               100.0                                                   ______________________________________                                    

One-tenth of a mL of the composition is administered directly into eacheye of a patient with glaucoma. The intraocular pressure issubstantially reduced.

EXAMPLE H Oral Liquid Composition

    ______________________________________                                        Ingredient           Amount/15 mL Dose                                        ______________________________________                                        Subject Compound 4   15        mg                                             Chlorpheniramine maleate                                                                           4         mg                                             Propylene glycol     1.8       g                                              Ethanol (95%)        1.5       mL                                             Methanol             12.5      mg                                             Eucalyptus oil       7.55      mg                                             Flavorants           0.05      mL                                             Sucrose              7.65      g                                              Carboxymethylcellulose (CMC)                                                                       7.5       mg                                             Microcrystalline cellulose and                                                                     187.5     mg                                             Sodium CMC (Avicel RC 591 ®)                                              Polysorbate 80       3.0       mg                                             Glycerin             300       mg                                             Sorbitol             300       mg                                             FD&C Red #40 dye     3         mg                                             Sodium saccharin     22.5      mg                                             Sodium phosphate monobasic                                                                         44        mg                                             Sodium citrate monohydrate                                                                         28        mg                                             Purified Water       q.s.                                                     Total =              15        mL                                             ______________________________________                                    

One 15 mL dose of the liquid composition is swallowed by a patient withnasal congestion and runny nose due to allergic rhinitis. The congestionand runny nose are effectively reduced.

EXAMPLE J Oral Liquid Composition

    ______________________________________                                        Ingredient         Amount/15 mL Dose                                          ______________________________________                                        Subject Compound 2 30        mg                                               Sucrose            8.16      g                                                Glycerin           300       mg                                               Sorbitol           300       mg                                               Methylparaben      19.5      mg                                               Propylparaben      4.5       mg                                               Menthol            22.5      mg                                               Eucalyptus oil     7.5       mg                                               Flavorants         0.07      mL                                               FD&C Red #40 dye   3.0       mg                                               Sodium saccharin   30        mg                                               Purified water     q.s.                                                       Total =            15        mL                                               ______________________________________                                    

One 15 mL dose of the alcohol-free liquid medication is swallowed by apatient with nasal congestion. The congestion is substantiallydiminished.

EXAMPLE K

For the relief of nasal congestion due to the common cold, hay fever, orother upper respiratory allergies, or associated with sinusitis;relieves runny nose, sneezing, and itchy watery eyes as may occur inallergic rhinitis. Restores freer breathing through the nose. Adults 12and over take one tablet every four hours.

    ______________________________________                                                              mg/tablet                                               ______________________________________                                        chlorpheniramine maleate, USP                                                                         4      mg                                             Subject Compound 1      4                                                     microcrystalline cellulose, NF                                                                        130                                                   starch 1500, NF         100                                                   magnesium stearate, USP 2                                                     total                   240    mg                                             ______________________________________                                    

EXAMPLE L

For the relief of symptoms associated with allergic rhinitis such assneezing, rhinorrhea, and nasal congestion. Adults 12 and over take onetablet every twelve hours.

    ______________________________________                                                               mg/tablet                                              ______________________________________                                        loratadine               5      mg                                            Subject Compound 2       12                                                   hydroxypropyl methylcellulose, USP                                                                     12                                                   magnesium stearate, USP  2                                                    lactose anhydrous, USP   200                                                  total                    231    mg                                            ______________________________________                                    

EXAMPLE M

For relief of symptoms associated with the common cold, sinusitis, orflu including nasal congestion, headache, fever, body aches, and pains.Adults 12 and over take two caplets every twelve hours.

    ______________________________________                                                               mg/caplet                                              ______________________________________                                        naproxen sodium anhydrous, USP                                                                         220    mg                                            Subject Compound 3       6                                                    hydroxypropyl methylcellulose, USP                                                                     6                                                    magnesium stearate, USP  2                                                    povidone K-30, USP       10                                                   talc, USP                12                                                   microcrystalline cellulose, NF                                                                         44                                                   total                    300    mg                                            ______________________________________                                    

EXAMPLE N

For relief of nasal/sinus congestion and pressure, sinus headache painassociated with sinusitis, hay fever, upper respiratory allergies, orthe common cold. Adults 12 and over take one tablet every six hours.

    ______________________________________                                                               mg/tablet                                              ______________________________________                                        acetaminophen, USP       500    mg                                            Subject Compound 4       6                                                    hydroxypropyl methylcellulose, USP                                                                     6                                                    silicon dioxide, colloidal, NF                                                                         30                                                   pregelatinized starch, NF                                                                              50                                                   magnesium stearate, USP  4                                                    total                    596    mg                                            ______________________________________                                    

EXAMPLE N

For the relief of symptoms associated with allergic rhinitis such assneezing, rhinorrhea, nasal congestion, sinus pain, and headache. Adults12 and over take two caplets every twelve hours.

    ______________________________________                                                               mg/caplet                                              ______________________________________                                        naproxen sodium anhydrous, USP                                                                         220    mg                                            loratadine               2.5                                                  Subject Compound 5       6                                                    hydroxypropyl methylcellulose, USP                                                                     6                                                    magnesium stearate, USP  2                                                    povidone K-30, USP       10.5                                                 talc, USP                12                                                   microcrystalline cellulose, NF                                                                         44                                                   total                    303    mg                                            ______________________________________                                    

EXAMPLE O

For the relief of symptoms due to the common cold, flu, hay fever, orother upper respiratory allergies, or associated with sinusitis;relieves runny nose, sneezing, and itchy watery eyes as may occur inallergic rhinitis. Relieves headache, fever, body aches, and pains.Restores freer breathing through the nose. Adults 12 and over take twotablets every twelve hours.

    ______________________________________                                                               mg/tablet                                              ______________________________________                                        naproxen sodium anhydrous, USP                                                                         220    mg                                            chlorpheniramine maleate, USP                                                                          6                                                    Subject Compound 1       6                                                    hydroxypropyl methylcellulose, USP                                                                     12                                                   magnesium stearate, USP  2                                                    povidone K-30, USP       10                                                   talc, USP                12                                                   microcrystalline cellulose, NF                                                                         44                                                   total                    312    mg                                            ______________________________________                                    

EXAMPLE P

For the relief of symptoms associated with allergic rhinitis such assneezing, rhinorrhea, nasal congestion, sinus pain, and headache. Adults12 and over take two tablets every six hours.

    ______________________________________                                                               mg/tablet                                              ______________________________________                                        acetaminophen, USP       500    mg                                            loratadine               1.3                                                  Subject Compound 5       3                                                    hydroxypropyl methylcellulose, USP                                                                     3                                                    silicon dioxide, colloidal, NF                                                                         30                                                   pregelatinized starch, NF                                                                              50                                                   magnesium stearate, USP  2.7                                                  total                    590    mg                                            ______________________________________                                    

EXAMPLE Q

For the relief of minor aches, pains, headache, muscular aches, sorethroat pain, and fever associated with a cold or flu. Relieves nasalcongestion, cough due to minor throat and bronchial irritations, runnynose, and sneezing associated with the common cold. Adults 12 and overtake one fluid ounce every six hours.

    ______________________________________                                                              mg/fl oz                                                ______________________________________                                        acetaminophen, USP      1000    mg                                            doxylamine succinate, USP                                                                             12.5                                                  dextromethorphan hydrobromide,                                                                        30                                                    USP                                                                           Subject Compound 2      6                                                     Dow XYS-40010.00 resin  3                                                     high fructose corn syrup                                                                              16000                                                 polyethylene glycol, NF 3000                                                  propylene glycol, USP   3000                                                  alcohol, USP            2500                                                  sodium citrate dihydrate, USP                                                                         150                                                   citric acid, anhydrous, USP                                                                           50                                                    saccharin sodium, USP   20                                                    flavor                  3.5                                                   purified water, USP     3500                                                  total                   29275   mg                                            ______________________________________                                    

EXAMPLE R

For the relief of minor aches, pains, headache, muscular aches, sorethroat pain, and fever associated with a cold or flu. Relieves nasalcongestion, cough due to minor throat and bronchial irritations, runnynose, and sneezing associated with the common cold. Adults 12 and overtake one fluid ounce every six hours.

    ______________________________________                                                              mg/fl oz                                                ______________________________________                                        naproxen sodium anhydrous, USP                                                                        220     mg                                            doxylamine succinate, USP                                                                             12.5                                                  dextromethorphan hydrobromide,                                                                        30                                                    USP                                                                           Subject Compound 1      6                                                     Dow XYS-40010.00 resin  3                                                     high fructose corn syrup                                                                              16000                                                 polyethylene glycol, NF 3000                                                  propylene glycol, USP   3000                                                  alcohol, USP            2500                                                  sodium citrate dihydrate, USP                                                                         150                                                   citric acid, anhydrous, USP                                                                           50                                                    saccharin sodium, USP   20                                                    flavor                  3.5                                                   purified water, USP     3800                                                  total                   28795   mg                                            ______________________________________                                    

Other examples of combination actives are contemplated. Examples ofmedicaments which can be combined with the primary active are includedin U.S. Pat. No. 4,552,899 to Sunshine, et al., hereby incorporated byreference. All other references referred to throughout thisspecification are hereby incorporated by reference.

While particular embodiments of the subject invention have beendescribed, it will be obvious to those skilled in the art that variouschanges and modifications of the subject invention can be made withoutdeparting from the spirit and scope of the invention. It is intended tocover, in the appended claims, all such modifications that are withinthe scope of this invention.

What is claimed is:
 1. A pharmaceutical composition comprising thecompound having the following structure: ##STR11## wherein: (a) R isunsubstituted alkanyl or alkenyl having from 1 to about 3 carbonatoms;(b) R' is selected from the group consisting of hydrogen;unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms;unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms;hydroxy; thiol; cyano; and halo; (c) R" is selected from the groupconsisting of hydrogen, methyl, ethyl and i-propyl;and one or moreactives chosen from the group consisting of an antitussive, mast cellstabilizer, LT antagonist, expectorant/muycolytic, antioxidant orradical inhibitor, steroid, bronchodilator, antiviral, analgesic,antiinflammatory, gastrointestinal and ocular active.
 2. Apharmaceutical composition according to claim 1 further comprising ananalgesic.
 3. A pharmaceutical composition according to claim 1 furthercomprising an antiinflammatory.
 4. A pharmaceutical compositionaccording to claim 1 further comprising an antihistamine.
 5. Apharmaceutical composition according to claim 1 further comprising anmuycolytic/expectorant.
 6. A pharmaceutical composition according toclaim 1 further comprising an antitussive.
 7. A pharmaceuticalcomposition according to claim 1 further comprising a mast cellstabilizer.
 8. A pharmaceutical composition according to claim 1 furthercomprising a LT antagonist.
 9. A pharmaceutical composition according toclaim 1 further comprising an antioxidant or radical inhibitor.
 10. Apharmaceutical composition according to claim 1 further comprisingasteroid.
 11. A pharmaceutical composition according to claim 1 furthercomprising a bronchodilator.
 12. A pharmaceutical composition accordingto claim 1 further comprising an antitussive.
 13. A pharmaceuticalcomposition according to claim 1 further comprising an antiviral.
 14. Apharmaceutical composition according to claim 1 further comprising anocular drug.
 15. A pharmaceutical composition according to claim 15further comprising a gastrointestinal active.